The Evolving Landscape of ADHD Treatment
For decades, stimulant medications like methylphenidate and amphetamines have been the first-line treatment for Attention-Deficit/Hyperactivity Disorder (ADHD) [1.3.6]. While effective for many, a significant portion of individuals either don't respond well, experience intolerable side effects, or have co-occurring conditions that make stimulants unsuitable [1.5.1, 1.4.8]. This has led to a growing interest in non-stimulant alternatives, which offer different mechanisms of action and side effect profiles. Unlike stimulants, non-stimulants are not controlled substances and generally have a lower potential for abuse [1.3.6, 1.5.1]. The field is actively evolving, with several new medications recently entering the market or progressing through clinical trials.
Onyda XR: A New Liquid Option
In May 2024, the U.S. Food and Drug Administration (FDA) approved Onyda XR (clonidine hydrochloride) extended-release oral suspension [1.2.2, 1.2.4]. This marked the introduction of the first and only liquid non-stimulant medication for ADHD [1.2.1, 1.2.6]. It is approved for use in pediatric patients aged six and older, either as a standalone (monotherapy) treatment or in conjunction with a stimulant medication [1.2.4, 1.2.5].
Developed by Tris Pharma, Onyda XR utilizes a proprietary technology to provide a smooth, extended-release profile with the convenience of once-daily nighttime dosing [1.2.3, 1.2.6]. As a centrally acting alpha-2 adrenergic agonist, it works differently than many other ADHD drugs by modulating neurotransmitter release in the prefrontal cortex, which is crucial for attention and impulse control [1.2.5, 1.6.7]. This mechanism is shared with another non-stimulant, guanfacine [1.2.5]. Because it is a liquid, it offers a valuable alternative for patients who have difficulty swallowing pills.
Qelbree (Viloxazine): A Novel SNRI
Approved by the FDA for children in 2021 and adults in 2022, Qelbree (viloxazine) represents another significant advancement [1.6.6]. Qelbree is a selective norepinephrine reuptake inhibitor (SNRI), working to increase the levels of norepinephrine, a key neurotransmitter involved in regulating attention and behavior [1.3.3, 1.3.5]. While its precise mechanism is still being fully understood, this action in the brain helps improve focus and reduce impulsivity and hyperactivity [1.3.3, 1.3.8].
Viloxazine was originally used as an antidepressant in Europe before being repurposed and reformulated as an extended-release capsule for ADHD [1.3.4]. Studies suggest it may have a faster onset of action than the older SNRI, atomoxetine (Strattera), with some patients seeing benefits within two to four weeks [1.4.1, 1.4.7]. It also has a low potential for abuse and is not a controlled substance [1.3.7].
How Do New Non-Stimulants Compare?
Choosing an ADHD medication is a highly individualized decision made with a healthcare provider. The new non-stimulants offer distinct advantages and disadvantages compared to older medications.
Comparison of ADHD Medications
| Medication Category | Examples | Mechanism of Action | Key Characteristics |
|---|---|---|---|
| Stimulants | Adderall, Ritalin, Vyvanse | Increase dopamine and norepinephrine | Fast-acting, high efficacy; potential for side effects like insomnia, appetite suppression; controlled substance with abuse potential [1.5.1]. |
| Older Non-Stimulants (SNRIs) | Strattera (atomoxetine) | Selective norepinephrine reuptake inhibitor | 24-hour coverage; may take 4-6 weeks for full effect; not a controlled substance [1.4.3, 1.6.7]. |
| Newer Non-Stimulants (SNRIs) | Qelbree (viloxazine) | Selective norepinephrine reuptake inhibitor | Faster onset than Strattera (2-4 weeks); flexible dosing (capsule can be opened); not a controlled substance [1.4.7, 1.6.4]. |
| Alpha-2 Agonists | Intuniv (guanfacine), Kapvay (clonidine), Onyda XR (clonidine) | Modulates norepinephrine signaling in the prefrontal cortex | Often used for hyperactivity, impulsivity, and emotional dysregulation; can be sedating; can be used alone or with stimulants [1.2.5, 1.6.7]. |
Real-world studies have begun to compare these options directly. One retrospective analysis found that patients showed significantly greater improvement in ADHD symptoms and preferred viloxazine (Qelbree) over atomoxetine (Strattera) [1.4.1, 1.4.2]. The study also noted viloxazine's more rapid effects [1.4.4]. Onyda XR, being a liquid form of clonidine, provides a new delivery method for a well-established mechanism, which can be particularly beneficial for children or those who cannot swallow pills [1.2.3].
On the Horizon: Centanafadine
Looking ahead, another promising non-stimulant, centanafadine, is currently under investigation [1.7.4]. If approved by the FDA, it would be the first triple reuptake inhibitor for ADHD, working on norepinephrine, dopamine, and serotonin [1.2.7]. Phase 3 trials have shown it to be effective in reducing ADHD symptoms in adults, adolescents, and children, with a generally tolerable side-effect profile [1.6.1, 1.7.7]. Common side effects included decreased appetite and headache [1.6.1]. Because its dopamine action is less potent than that of stimulants, it is expected to have a lower abuse liability [1.6.1]. As of late 2025, Otsuka Pharmaceutical is expected to discuss trial results with health authorities [1.7.7].
Conclusion: Expanding the Toolkit for ADHD Management
The arrival of new non-stimulant medications like Onyda XR and Qelbree, along with promising candidates like centanafadine, marks a critical expansion of the treatment toolkit for ADHD. These therapies provide vital alternatives for the roughly 30% of individuals who do not find success with stimulants, as well as those who struggle with side effects, co-existing conditions like anxiety, or concerns about abuse potential [1.5.1, 1.4.8]. By offering different mechanisms of action, from SNRIs to alpha-2 agonists, these newer drugs allow for a more personalized and nuanced approach to managing ADHD symptoms across a patient's lifespan.
For more information on approved medications, visit the U.S. Food and Drug Administration (FDA) website.
